The extreme hyper‐reactivity of selected cysteines drives hierarchical disulfide bond formation in serum albumin
Alessio Bocedia b, Raffaele Fabrinia b, Jens Zacho Pedersenc d, Giorgio Federicia b, Federica Iavaronee f, Claudia Martellie f, Massimo Castagnolae f, Giorgio Riccia b✉
- aDepartment of Chemical Sciences and Technologies University of Rome ‘Tor Vergata’ Italy
- bDepartment of Chemical Sciences and Technologies, University of Rome 'Tor Vergata', Italy
- cDepartment of Biology University of Rome ‘Tor Vergata’ Italy
- dDepartment of Biology, University of Rome 'Tor Vergata', Italy
- eInstitute of Biochemistry and Clinical Biochemistry Catholic University and/or Institute for Molecular Recognition National Research Council Rome Italy
- fInstitute of Biochemistry and Clinical Biochemistry, Catholic University and/or Institute for Molecular Recognition, National Research Council, Rome, Italy
- ✉Corresponding author
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Abstract
After mild reduction of serum albumin, seven among the 34 cysteines forming the disulfide network displayed a surprising hyper‐reactivity. Compared to the thiol group of glutathione, the average reactivity of these cysteines towards disulfides and thiol reagents was more than 100 times higher. Using mass spectrometry and kinetic data, we identified all these unusual residues, with Cys75, Cys123 and Cys264 showing the highest reactivity. This effect was mainly due to a lowpKaof the sulfhydryl groups and may explain the very fast formation of early disulfides in the nascent protein suggesting the existence of a hierarchical propensity to form such covalent links in selected regions during oxidative folding. An identical pattern of hyper‐reactive cysteines was found in albumins from six different mammals. This hyper‐reactivity is much higher than the one found in other proteins containing multiple cysteines only devoted to structural disulfide bonds. It is possible that such hyper‐reactive cysteines could also be present in other proteins, although their existence has been completely ignored so far.
TL;DRAfter mild reduction of serum albumin, seven among the 34 cysteines forming the disulfide network displayed a surprising hyper‐reactivity, which may explain the very fast formation of early disulfides in the nascent protein suggesting the existence of a hierarchical propensity to form such covalent links in selected regions during oxidative folding. (Semantic Scholar)